Methods of preventing and reducing the size of Striae distensae lesions

ABSTRACT

Striae distensae lesions may be prevented and/or reduced in size by topically applying to the skin affected with the lesions an effective amount of a retinoid, preferably retinoic acid, preferably by daily application in a dermatologically acceptable vehicle, such as a cream base, at a concentration of about 0.025 to 0.1 weight percent retinoic acid. When applied during the striae rubrae stage, the retinoid may be effective to prevent the formation of striae albae lesions, and when applied in either stage, the retinoid may be effective to reduce the width and depth of the lesions, with improved texture and softness.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. patent applicationSer. No. 07/402,271, filed Sep. 1, 1989 now U.S. Pat. 5,134,163 andcorresponds to PCT/US90/04939, filed Aug. 30, 1990, now InternationalPublication No. WO 91/03240.

FIELD OF THE INVENTION

The present invention is directed to methods of preventing and/orreducing the size of lesions of striae distensae. More particularly, theinvention is directed to a method of preventing the formation of stridealbae and a method of reducing the size of lesions of both striae albaeand striae rubrae.

BACKGROUND OF THE INVENTION

Striae distensae are very common lesions. They are present in mosthealthy adult women, having originated either during puberty or at thetime of the first pregnancy. Stretching of the skin, as in rapid weightgain, or mechanical stress, as in weight lifting, often precedes theirdevelopment. About 50 percent of pregnant women will develop theselesions, often referred to as stretch marks, on thighs, abdomen andbreasts, starting at about 3 to 4 months of gestation. However, suchlesions are also noted in cachectic states, for example in tuberculosisand typhoid fever, and they have also been noted after intense slimmingdiets.

The pathogenesis of stride distensae lesions is unclear. Some pregnantwomen do not develop the lesions; lesions have not been producedexperimentally, and there is no animal model.

Clinicians are aware that striae distensae evolve over time passingthrough an early phase of inflammation (striae rubrae) and ending in thetypical white stretch mark (striae albae). The striae rubrae are red,slightly elevated, linear lesions that may be tender. Later, the lesionsflatten and the redness fades, leaving a permanent, wavy depression,which is the striae albae. The striae albae lesions may be 5 to 15 mmwide, depressed with a crinkly surface. These are the stretch markswhich last for life, since to date there has been no known treatment.

The histopathology of striae, which always have the same appearanceregardless of cause, has generated much dispute. However, P. Zheng, etal., "Anatomy of Striae," British Journal of Dermatology, 112:185-193(1985) present evidence that striae albae are true scars resulting froman earlier inflammatory process that destroys elastic fibers. They arenot formed by stress-induced rupture of the dermal fibrous network.

Retinoids, particularly retinoic acid, have been previously appliedtopically to the skin for the treatment of many skin disorders. See, forexample the review of Thomas et al., "The Therapeutic Uses of TopicalVitamin A Acid," Journal of the American Academy of Dermatology,4:505-513 (1981). It is known that tretinoin has an anti-inflammatoryaction useful in ameliorating chronic dermatoses such as psoriasis andlichen planus.

According to my U.S. Pat. Nos. 4,603,146; 4,877,805 and 4,888,342,topical retinoids have been effective to stimulate formation of newcollagen fibers, generate new blood vessels, correct abnormalities inelastic fibers, and eliminate neoplastic growths in chronicallysundamaged skin. Retinoic acid is used world-wide to retard and reversephotodamage from excessive exposure to ultra-violet radiation insunlight.

The literature also reports the improvement of post-ache, elevated,hypertrophic scars of the back with topical retinoic acid. Thesehypertrophic scars have a very different origin, following severe cysticlesions, resulting in a high increase in collagen. In striae distensaethe opposite happens; there is loss of collagen with atrophic scarring.

BRIEF SUMMARY OF THE INVENTION

According to the present invention, it has been found that striaedistensae lesions may be prevented and reduced in size by applying aretinoid, preferably tretinoin, topically to the area of the skinaffected or likely to be affected with the lesions. The retinoid isapplied in a dermatologically acceptable vehicle, such as a cream base,preferably in a concentration of about 0.025 to 0.1 weight percent inthe case of tretinoin, generally by daily application. When applied inthe striae rubrae stage, the retinoid prevents or reduces the formationof striae albae. When applied in the striae albae stage, the scarsbecome less noticeable, less wrinkled, and softer, though the lesions donot disappear altogether. When applied early in pregnancy before anyclinical change, stretch marks may be almost completely prevented.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The retinoid, preferably retinoic acid, also referred to as Vitamin Aacid, and more particularly the all-trans isomer of retinoic acid, alsoknown as tretinoin, is applied topically to striae distensae lesionsaccording to the present invention. The topical application may be byspreading on with the fingers or by use of a suitable applicator such asa cotton swab.

Retinoids have been defined narrowly as comprising simply vitamin A(retinol) and its derivatives such as vitamin A aldehyde (retinal),vitamin A acid (retinoic acid), comprising the so called naturalretinoids. However, subsequent research has resulted in a much largerclass of chemical compounds that are termed retinoids due to theirbiological similarity to vitamin A and its derivatives. Compounds usefulin the present invention include all natural and/or synthetic analogussof vitamin A or retinol-like compounds which possess the biologicalactivity of vitamin A in the skin, particularly the prevention andreduction in size of striae distensae lesions, among other effects.Accordingly, as used herein for purposes of the present invention, theterm "retinoid" will be understood to include any of the foregoingcompounds. Examples of suitable retinoids for use in the presentinvention are set forth in Table I, although it will be understood thatthe invention is not limited thereto.

TABLE I Chemical, Common and/or Commercial Name

Isotretinoin 13-cis-retinoic acid ACCUTANE

Etretinate TEGISON(all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester

Etretin(all-E)-9-(4-methoxy-2,3,6,-trimethylphenyl)-3,7-dimethyl-2,4,6,8,-nonatetraenoicacid

MotretinideN-ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenamide

(E,E)-9-(2,6-dichloro-4-methoxy-3-methylphenyl)3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester

7,8-didehydroretinoic acid

(E,E)-4-[2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-butadienyl]benzoic acid

(E)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-hexatrienyl]benzoic acid

(all-E) -3,7-dimethyl-9- (3-thienyl)-2,4,6,8-nonatetraenoic acid

(E,E,E)-3-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2,4,6-octatrienoicacid

(E)-6-[2-(2,6,6-trimethyl-l-chclohexen-1-yl)ethenyl]-2-naphthalenecarboxylicacid

(E,E,E)-7-(2,3-dihydro-1,1,3,3-tetramethyl-1H-inden-5-yl)-3-methyl-2,4,6-octatrienoicacid

(E)-4-(2,3-dihydro-1,1,3,3,-tetramethyl-1H-inden-5-yl)-1-propenyl]benzoic acid

TTNPB(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl]benzoic acid

(E)-4-[2-(5,6,7,8-tetrahydro-3-methyl-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid

(E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(1-methyl-2-phenylethyl)naphthalene

6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylicacid

(E)-6-[2-[4-(ethylsulfonyl)phenyl-1-methylethenyl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene

4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid

(E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl-[4-tetrazol-5-yl)phenyl]-1-propene

(E)-4-[2-(5,6,7,8,-tetrahydro-7-hydroxy-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzyl alcohol

AM-802-(4-Carboxybenzamido)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene

AM-5802-[N-4-(Carboxyphenyl)carbamoyl]-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene

CH-55 1-[3,5-(Di-tert-butyl)benzoyl]-2-(4Carboxyphenyl)ethene

TTNT 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo(b)thiophene carboxylic acid

TTNF 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo(b)furancarboxylic acid

TTNI2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-indolecarboxylicacid

TTNN 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-naphthalenecarboxylic acid

p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid

Esters or amides of 13-trans retinoic acid or 13-cis retinoic acidwherein the --OH group of the carboxylic acid (--COOH) group issubstituted by --OR¹ or --NR² R³ wherein R¹ R² and R³ are such thatthese esters or amides can be converted to 13-trans retinoic acid or13-cis retinoic acid through hydrolysis, metabolism, cleavage, etc.

Also encompassed within the term "retinoid" are geometric andstereoisomers of the retinoids. While the specific examples below usetretinoin (all-trans retinoic acid), isotretinoin (13-cis-retinoic acid)may also be used, although somewhat higher concentrations are needed toobtain equivalent results.

Retinoids may be formulated in bland, moisturizing bases, such as creamsor ointments, usually in low concentrations, although higherconcentrations may be used for darker skins. The retinoid shouldpreferably be applied in an amount which is not excessively irritatingto the skin. Other non-toxic, dermatologically acceptable vehicles orcarriers in which retinoids are stable will be evident to those ofordinary skill in the art. In general, emollient or lubricatingvehicles, such as oleaginous substances, which help hydrate the skin arepreferred. As used herein, the term "emollient" will be understood torefer to the non-irritating character of the composition as a whole.That is, the nature of the vehicle and amount of retinoid therein shouldbe selected so as to provide a sub-irritating dose for topicalapplication. Volatile vehicles which dry or otherwise harm the skin,such as alcohol and acetone, should be avoided.

An ointment base (without water) is preferred in the winter and insubjects with very dry skin. Examples of suitable ointment bases arepetrolatum, petroldrum plus volatile silicones, lanolin, and water inoil emulsions, such as Eucerin (Beiersdorf).

In warm weather and often for younger persons, oil in water emulsion(cream) bases, are preferred. Examples of suitable cream bases are NiveaCream (Beiersdorf), cold cream (USP), Purpose Cream (Johnson & Johnson),hydrophilic ointment (USP), and Lubriderm (Warner-Lambert).

Some retinoids are mild irritants and may cause redness and scaling,which may be accompanied by some tenderness and tightness. Thesereactions are transient and quickly disappear when the applications arestopped. However, the skin rapidly accommodates, and even when retinoidsare applied excessively to produce visible inflammation, the reactionslowly disappears leaving no permanent sequellae. Systemic sidereactions are unknown and are not to be expected from such lowconcentrations according to the present invention. Selection of anappropriate emollient vehicle will more readily allow the use of ahighly effective but sub-irritating does ot the retinoid.

Retinoic acid may be applied in any dermatologically acceptable vehiclesuch as a gel or a cream base. Retinoic acid in a cream base isavailable commercially for the treatment of ache from Johnson & Johnsonunder the trademark RETIN-A, which is available in concentrationsranging from 0,025 to 0.1 weight percent. Gel bases of RETIN-A are alsoavailable. Other suitable formulations will be apparent to those skilledin the art based upon the present disclosure.

For purposes of the present invention where the retinoid is retinoicacid, the retinoic acid is generally applied in a concentration of about0.025 to 0.1 weight percent of the total composition, and preferablyabout 0.25 to 0.1 weight percent of the composition. Such concentrationsare too low to cause birth defects (teratogenicity). Also,concentrations of 0.1 percent or less are insufficient to cause any sideeffects other than some minor early irritation to which the skingradually accommodates. No systemic effects have been reported in thetreatment of many millions of ache sufferers.

Generally, the topical applications are made once daily, although twicedaily or thrice weekly applications may prove beneficial or satisfactoryin some cases. Clinically significant improvement is usually seen after4 to 5 months of daily treatment. The width and depth of stretch marksis greatly reduced. Tenderness and redness are ameliorated.

For best results, the topical applications of retinoid are started inthe early red stage (striae rubrae) in the first few months afterconception. When started at this stage, not only will the lesions becomenarrower, shallower and much less noticeable, but permanent scarringwill be largely prevented in at least about half of the patientstreated. The prophylactic strategy of beginning the treatment of theinvention in early pregnancy yields optimal results. The treatmentshould continue at least until birth, and possibly for another fewmonths after birth, although the benefits of post-natal therapy arestill being investigated.

When the topical retinoid treatments of the present invention are notstarted until the lesions have reached the striae albae stage, it isstill possible to soften the scars, reduce their depth, and improve thetexture of the skin with the topical applications. In these cases, thedreaded and embarrassing stretch marks can be significantly reduced insize so that they are less noticeable. Old, long-standing striae albaelesions improve only slightly.

While applicant does not wish to be bound by any particular theory, itis believed that the mechanism of action of retinoids in preventing andreducing the size of stride distensae is due to two actions: (1)suppression of inflammation present in stride rubrae (we have shown thatthere is an intense inflammatory reaction in biopsies from striderubrae) and (2) stimulation of new collagen formation resulting inshallower, softer scars in both stride rubrae and stride albae.

The invention will now be illustrated in further detail by reference tothe following specific, non-limiting examples.

EXPERIMENTAL EXAMPLES

Over forty women with striae distensae were treated according to thepresent invention. The lesions on one side of the abdomen were treatedwith 0.05 to 0.1 percent RETIN-A cream, generally once daily, whileNivea Cream alone was applied to the other side of the abdomen as acontrol. Most of the forty test subjects were 3 to 5 months pregnant,showing stride rubrae. The remainder had stride albae of varyingduration, usually not greater than 5 years. Tretinoin was applied oncedaily at the start of therapy. This was sometimes increased to twicedaily in those who experienced little irritation.

In the cases where treatment was begun in the stride rubrae stage, abouthalf were greatly improved in comparison to the control. In three caseswhere treatment was started in the first few weeks of pregnancy beforeany evidence of striae distensae, the suppression of striae on thetreated side was impressive (almost complete) in two of the cases. Wherethe treatment did not begin until the striae albae stage, about onethird showed clinically significant improvement after 4 to 5 months ofdaily treatment. The improved women were impressed with the results. Theonly side effects have been some early irritation, which was temporary.

In the four cases which were biopsied, the histology showed nearlynormal skin, with good collagen bundles, on the side treated withRETIN-A. The control side showed fine fibers, tightly packed in parallelarray, typical of a scar.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributed thereof, andaccordingly, reference should be made to the appended claims, ratherthan to the foregoing specification as indicating the scope of theinvention.

I claim:
 1. A method of eliminating or reducing the size of striaedistensae lesions comprising applying topically to the area of the skinaffected with said lesions a composition comprising an amount of aretinoid effective to reduce or eliminate said lesions.
 2. A methodaccording to claim 1 wherein said composition is applied about oncedaily to said area.
 3. A method according to claim 1 wherein saidretinoid is applied in an emollient vehicle.
 4. A method according toclaim 1, wherein said composition is applied in a dematologicallyacceptable vehicle containing said retinoid at a concentrationequivalent to about 0.025 to 0.1 weight percent retinoic acid.
 5. Amethod according to claim 4 wherein said vehicle is a cream or gel base.6. A method according to claim 1 wherein said composition is applied tothe skin in the striae rubrae stage of the lesions to reduce the size ofthe lesions and prevent the formation of striae albae.
 7. A methodaccording to claim 1 wherein said composition is applied to the skin inthe striae albae stage of the lesions to reduce the size of the lesions.8. A method of preventing the formation of significant striae distensaeof the abdomen comprising applying topically to the skin of the abdomenan effective amount of a retinoid during early pregnancy prior toclinical appearance of lesions.